Prevalence and clinical features of bone morphogenetic protein receptor type 2 mutation in Korean idiopathic pulmonary arterial hypertension patients: The PILGRIM explorative cohort

Albert Youngwoo Jang, Bo-Gyeong Kim, Sunkoo Kwon, Jiyoung Seo, Hyung Kwan Kim, Hyuk-Jae Chang, Sung-A Chang, Goo-Yeong Cho, Sang Jae Rhee, Hae Ok Jung, Kyung-Hee Kim, Hye Sun Seo, Kye Hun Kim, Jinho Shin, Jun Soo Lee, Minsu Kim, Young Jae Lee, Wook-Jin Chung, Albert Youngwoo Jang, Bo-Gyeong Kim, Sunkoo Kwon, Jiyoung Seo, Hyung Kwan Kim, Hyuk-Jae Chang, Sung-A Chang, Goo-Yeong Cho, Sang Jae Rhee, Hae Ok Jung, Kyung-Hee Kim, Hye Sun Seo, Kye Hun Kim, Jinho Shin, Jun Soo Lee, Minsu Kim, Young Jae Lee, Wook-Jin Chung

Abstract

Background: Pulmonary arterial hypertension (PAH) is a progressive chronic disease with poor outcomes. One reason for poor prognosis is the lack of understanding regarding individual variability in response to treatment. Idiopathic PAH (IPAH) patients with bone morphogenetic protein receptor type 2 (BMPR2) mutations have distinct phenotypes that are crucial for individualized therapy but evidence regarding their prevalence and clinical features in the Korean population is lacking. Therefore, the present study aimed to screen Korean IPAH patients for BMPR2 mutations and analyze their clinical phenotypes.

Methods: We enrolled 73 unrelated IPAH patients for BMPR2 mutation screening between March 2010 to November 2015 from 11 hospitals in Korea. Thirty-three lineal family members from 6 families of BMPR2 mutation carriers were also screened.

Results: Among 73 patients, 16 (22%) had BMPR2 mutations. Mutation carriers were younger (27 vs. 47 years; p = 0.02) and had a higher mean pulmonary arterial pressure (mPAP) than non-carriers (64 vs. 51 mmHg; p<0.05). Of the 16 individuals with mutations, 5 deletion, 2 splice-site, 6 nonsense, and 3 missense mutations were found, among which, 9 were newly identified mutation types. Patients less than 30 years old had more BMPR2 mutations (44 vs. 14%; p = 0.04) and a higher mPAP (64 vs. 50 mmHg; p = 0.04) compared with those equaled to or over 30 years old. There were no differences in hemodynamic profiles or the proportion of BMPR2 mutation carriers between groups according to sex.

Conclusion: The prevalence of BMPR2 mutations in Korean IPAH patients was 22%. Mutation carriers were younger and had a poorer hemodynamic profile compared with the non-carriers.

Clinical trial registration: Clinicaltrials.gov NCT01054105.

Conflict of interest statement

All authors have no potential conflicts of interest to disclose.

Figures

Fig 1. Diagram for detailed enrollment.
Fig 1. Diagram for detailed enrollment.
The study population included 73 individuals with IPAH who were evaluated for BMPR2 mutations. Sixteen individuals were positive for BMPR2 mutation, among which 7 had at least one BMPR2 mutation-positive family member. Fifty-seven individuals were BMPR2 mutation carriers, whereas 17 were non-carriers. Abbreviations: PAH, pulmonary arterial hypertension; BMPR2, bone morphogenetic protein receptor type 2; IPAH, idiopathic pulmonary arterial hypertension.
Fig 2. The worldwide prevalence between BMPR2…
Fig 2. The worldwide prevalence between BMPR2 mutation carriers and non-carriers in patients with idiopathic or heritable pulmonary arterial hypertension.
The overall prevalence of BMPR2 mutation carriers in IPAH patients in Korea was 22%, which is higher than in China and lower than in Japan. BMPR2 = bone morphogenetic protein receptor type 2.

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